Choline Intake Raises TMAO From Gut Flora, Platelet Activation

Marlene Busko

April 27, 2017

CLEVELAND, OH — A study has shown for the first time in humans that ingesting oral dietary choline supplements can lead to increased plasma levels of the metabolite trimethylamine N-oxide (TMAO), and this correlates with platelet hyperresponsiveness[1].

Specifically, eight vegans/vegetarians and 10 omnivores were given oral choline supplements (500-mg choline bitartrate twice a day for 2 months) and their TMAO levels increased 10-fold. "Moreover, a striking dose-dependent association was observed between plasma TMAO levels and platelet function," Dr Weifel Zhu (Cleveland Clinic, OH) and colleagues report in their study that was published as a research letter om the April 25, 2017 issue of Circulation.

In a second part of the study, the 10 omnivores had a washout period and were given low-dose aspirin followed by the same choline supplements, but this time the increases in plasma levels of TMAO and platelet aggregation were dampened.

These findings show that the "gut microbial metabolite TMAO is directly linked to platelet function and enhanced thrombosis potential in humans, and being on a low-dose aspirin can serve as a therapeutic intervention to partially attenuate that risk," senior author Dr Stanley L Hazen (Cleveland Clinic, OH) told heartwire from Medscape.

Is Dietary Choline Prothrombotic?

Bacteria in the gut break down dietary phosphatidylcholine, choline, and L-carnitine into trimethylamine (TMA), which is metabolized into TMAO in the liver, Hazen explained.

In previous research, his team showed that plasma levels of TMAO are linked to the development of cardiovascular disease, and high levels increase the risk of a thrombotic event in patients with acute coronary syndrome. They recently showed that TMAO enhances platelet responsiveness in animal models.

Dietary carnitine comes largely from red meat, but choline comes from meat, dairy products, eggs, and other sources, and soy is a source of phosphatidylcholine (lecithin).

"It's a fallacy to think if you're a vegetarian or vegan you can't have a high TMAO," Hazen clarified. "There's a ton of choline in gallbladder juice, so you're constantly feeding choline to your gut microbes, even when you eat a cucumber sandwich."

The researchers enrolled 18 healthy subjects (seven men and 11 women) who had a mean age of 46 and were nonsmokers without hypertension, diabetes, or cardiovascular disease. The subjects received 450-mg choline a day for 2 months.

The mean levels of TMAO in the blood increased from 2.6 µmol/L at baseline to 27 µmol/L and 29 µmol/L at 1 month and 2 months, respectively, in the vegans/vegetarians. The levels increased from 2.5 µmol/L at baseline to 36 µmol/L and 27 µmoL/L, respectively in the omnivores.

The patients' platelets showed enhanced aggregation with a submaximal stimulus (5-µmol/L adenosine diphosphate), and this hyperresponsiveness increased with increasing levels of TMAO.

In the second part of the study, after a washout period, the 10 omnivores were given 81-mg aspirin each evening for a month, followed by 2 months of choline supplements, during which time the subjects continued on aspirin.

This time, the degree of TMAO elevation and platelet hyperresponsiveness were each attenuated. Aspirin lowered TMAO by about 40%.

"These studies argue that if you have a high TMAO—which is a clinically available test—you're clearly at heightened risk for experiencing clotting," said Hazan. "So maybe that's a primary-prevention group that not only should use more global preventive efforts but also should be on a baby aspirin."

TMAO is measured by mass spectrometry, and the test is available in reference labs such as the Cleveland HeartLab, he added.

The group recently showed that the inhibitor 3,3-dimethyl-1-butanol blocks this pathway and inhibits diet-dependent atherosclerosis in mouse models[2].

"This is an area we are focusing on—to try to block the microbial enzyme, as a way of treating heart disease," said Hazen. "That is something down the road as well."

The research was supported by grants from the National Institutes of Health and the Office of Dietary Supplements. Hazen is a coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. He is a paid consultant for Esperion and Procter & Gamble; has received research funds from Procter & Gamble, Pfizer, Roche Diagnostics, and Takeda; and may receive royalties for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Procter & Gamble, Cleveland HeartLab, Siemens, Esperion, and Frantz Biomarkers. Disclosures for the coauthors are listed in the paper.

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